The adhesion of pathogens to host cell surfaces is the initial and most critical step in their development of infection or disease. Several viral and bacterial families are known to utilize host sialic acid sugars for adherence or host-pathogen interactions (Lehmann et al, 2006). Sialic acid sugars are nonulosonic sugars, a family of nine-carbon α-keto acids. These molecules have been extensively investigated as drug targets.
However, there are currently a limited number of treatments available for viral and/or bacterial infections; unfortunately, many pathogens have developed resistance to the current medicines. Additionally, existing vaccination methods are not effective in guarding against all influenza virus infection, especially for newly emerging pandemic strains, as the coat of the virus changes continually and rapidly. These changes are predominantly found within surface epitopes of the abundant hemagglutinin (H) and neuraminidase (N) components, preventing their recognition by host antibodies. H and N are two large proteins on the viral particle surface that bind sialic acids of the host; the sialic acid binding activity of H mediates initial adherence to and entry into target cells, whereas N cleaves host sialic acids allowing the release of new progeny virus from infected cells, facilitating the invasion of other host cells (Moscona, 2005). The combination of various H and N components is the basis for classification of influenza A, with 16 H subtypes and 9 N subtypes identified so far. However, the sialic acid binding ability remains constant amongst all infective H and N variants formed through antigenic drift. In addition, many respiratory bacterial pathogens such as Pseudomonas aeruginosa, Hemophilus influenzae and Streptococcus pneumoniae produce neuraminidases (N). For the former, this N enzyme is required for biofilm formation and plays a key role in the initial stages of pulmonary infection, for example lung infections in cystic fibrosis patients (Soong et al., 2006).
Current antibiotics to treat influenza, such as Zanamivir and Oseltamivir, are sialic acid mimics that inhibit the function of N, thereby trapping progeny virus at the cell surface and limiting viral infection to one round of replication. They are rationally-designed synthetic derivatives, based on knowledge of the transition state of sialic acid and the 3-dimensional structure of N's binding pocket (Colman, 1994). However, the chemistries involved in producing these compounds are challenging, which presents a further obstacle in providing treatment (Ishikawa et al., 2009; Lagoja and Clercq, 2008).
As the threat of a global pandemic looms on the horizon, the development of more potent and effective pathogen inhibitors has gained in importance. However, compounds capable of treating or preventing pandemic disease remain elusive.